High-performance liquid chromatography(HPLC) was used to determine the content of three major components in Citri Reticulatae Semen(CRS), including limonin, nomilin, and obacunone. The chromaticity of the CRS sample during salt processing and stir-frying was measured using a color difference meter. Next, the relationship between the color and content of the salt-processed CRS sample was investigated through correlation analysis. By integrating the oil bath technique for processing simulation with HPLC, the changes in the relative content of nomilin and its transformation products were analyzed, with its structural transformation pattern during processing identified. Additionally, RAW264.7 cells were induced with lipopolysaccharides(LPSs) to establish an inflammatory model, and the anti-inflammatory activity of nomilin and its transformation product, namely obacunone was evaluated. The results indicated that as processing progressed, E~*ab and L~* values showed a downward trend; a~* values exhibited a slow increase over a certain period, followed by no significant changes, and b~* values remained stable with no significant changes over a certain period and then started to decrease. The limonin content remained barely unchanged; the nomilin content decreased, and the obacunone increased significantly. The changing trends in content and color parameters during salt-processing and stir-frying were basically consistent. The content of nomilin and obacunone was significantly correlated with the colorimetric values(L~*, a~*, b~*, and E~*ab), while limonin content showed no significant correlation with these values. By analyzing HPLC patterns of nomylin at different heating temperatures and time, it was found that under conditions of 200-250 ℃ for heating of 5-60 min, the content of nomilin significantly decreased, while the obacunone content increased pronouncedly. The in vitro anti-inflammatory activity results indicated that compared to the model group, the group with a high concentration of nomilin and the groups with varying concentrations of obacunone showed significantly reduced release of nitric oxide(NO)(P<0.01). When both were at the same concentration, obacunone showed better performance in inhibiting NO release. In this study, the obvious correlation between the color and content of major components during the processing of CRS samples was identified, and the dynamic patterns of quality change in CRS samples during processing were revealed. Additionally, the study revealed and confirmed the transformation of nomilin into obacunone during processing, with the in vitro anti-inflammatory activity of obacunone significantly greater than that of nomilin. These findings provided a scientific basis for CRS processing optimization, tablet quality control, and its clinical application.
Mice ; Animals ; Drugs, Chinese Herbal/pharmacology* ; RAW 264.7 Cells ; Limonins/chemistry* ; Chromatography, High Pressure Liquid ; Citrus/chemistry* ; Color ; Benzoxepins/chemistry* ; Anti-Inflammatory Agents/chemistry*

Immunotherapy has emerged as a revolutionary approach to treat immune-related diseases. Dendritic cells (DCs) play a pivotal role in orchestrating immune responses, making them an attractive target for immunotherapeutic interventions. Modulation of gene expression in DCs using genome editing techniques, such as the CRISPR-Cas system, is important for regulating DC functions. However, the precise delivery of CRISPR-based therapies to DCs has posed a significant challenge. While lipid nanoparticles (LNPs) have been extensively studied for gene editing in tumor cells, their potential application in DCs has remained relatively unexplored. This study investigates the important role of cholesterol in regulating the efficiency of BAMEA-O16B lipid-assisted nanoparticles (BLANs) as carriers of CRISPR/Cas9 for gene editing in DCs. Remarkably, BLANs with low cholesterol density exhibit exceptional mRNA uptake, improved endosomal escape, and efficient single-guide RNA release capabilities. Administration of BLAN_mCas9/gPD-L1 results in substantial PD-L1 gene knockout in conventional dendritic cells (cDCs), accompanied by heightened cDC1 activation, T cell stimulation, and significant suppression of tumor growth. The study underscores the pivotal role of cholesterol density within LNPs, revealing potent influence on gene editing efficacy within DCs. This strategy holds immense promise for the field of cancer immunotherapy, offering a novel avenue for treating immune-related diseases.

Aim To investigate the effects of Ixerin Z,a sesquiterpene lactone from Ixeris sonchifolia,on bone-lipid metabolic imbalance in ApoE-/-mice and to elu-cidate its molecular mechanisms.Methods A mouse model of ApoE-/-was induced using a high-fat diet,followed by eight weeks of Ixerin Z administration at doses of 1 and 10 mg·kg-1.Serum markers related to bone-lipid metabolism and inflammatory cytokines were quantified.Bone mineral density,biomechanical prop-erties,bone tissue morphology,and bone microstructure changes were analyzed.Computational molecular doc-king was performed to identify potential target proteins of Ixerin Z,and its regulatory effects on bone-lipid me-tabolism were investigated.Results Treatment with Ixerin Z markedly decreased the serum levels of total cholesterol,triglycerides,TNF-α,and IL-1β in ApoE-/-mice.It significantly improved bone mineral density,enhanced biomechanical strength,restored tra-becular structure,and reduced fat accumulation in bone tissue.Investigations revealed that Ixerin Z activated PPARα,thereby promoting fatty acid β-oxidation in bone tissue,and stimulating the Wnt/β-Catenin signa-ling pathway to facilitate bone formation.Furthermore,Ixerin Z suppressed the OPG/RANKL/NF-κB signaling pathway,leading to reduced bone resorption,independ-ent of PPARα activation.Conclusions Ixerin Z dem-onstrates potent therapeutic effects on bone-lipid meta-bolic imbalance in ApoE-/-mice.The mechanism in-volves activating PPARα to promote fatty acid β-oxida-tion in bone tissue,activating PPARα/Wnt/β-Catenin signaling pathway to promote bone formation,and in-hibiting OPG/RANKL/NF-κB signaling pathway to re-duce bone resorption.

Objective:To evaluate the feasibility of transjugular transcatheter tricuspid valve replacement (TTVR) using the LuX-Valve Plus system (Ningbo Jenscare Scientific, China) for the treatment of severe tricuspid regurgitation in real-world clinical settings.Methods:This prospective study enrolled 81 patients with severe ricuspid regurgitation (≥3+) who underwent TTVR with the LuX-Valve Plus system at the Department of Cardiology, West China Hospital of Sichuan University between May 2022 and March 2024. Among them, 44 patients were from a compassionate-use study, and 37 were from two premarket clinical trials. Baseline clinical data, preprocedural imaging, procedural outcomes, and postprocedural follow-up data were collected. The primary endpoint events included device success, procedural success, and 30 d composite adverse events.Results:The age of the cohort was (74.5±7.8) years, with 54 females (67%). Device success and procedural success rates were both 90% (73/81). Post-procedural tricuspid regurgitation improved, with a 6% (5/81) incidence of moderate-to-severe paravalvular leakage. The rate of permanent pacemaker implantation was 12% (10/81), of which 5% (4/81) had pre-existing indications for pacemaker implantation. Major bleeding events occurred in 10% (8/81) of patients, and the 30 d composite endpoint rate was 25% (20/81).Conclusion:TTVR using the LuX-Valve Plus system demonstrates promising feasibility for high-risk surgical patients with severe tricuspid regurgitation, effectively reducing or eliminating regurgitation with acceptable safety. However, challenges remain in reducing risks of major adverse events, including permanent pacemaker implantation and severe bleeding.

AIM To study the chemical constituents from ethyl acetate fraction of Balanophora harlandii Hook.f.and their tyrosinase inhibitory activity.METHODS Separation and purification were performed using silica gel,MCI,ODS,Sephadex LH-20 and semi-preparative HPLC,then the structures of obtained compounds were identified by physicochemical properties and spectral data.The monophenolase inhibitory activity was determined by the tyrosinase-catalyzed oxidation of L-tyrosine.RESULTS Twenty-four compounds were isolated and identified as sesamin(1),methyl caffeate(2),quercetin(3),5,7-dihydroxychromanone(4),methyl 3,4-dihydroxybenzoate(5),esculetin(6),kaempferol(7),naringenin(8),pyrogallic acid(9),pinosylvin(10),methyl propionate(11),caffeic acid(12),saccharinol(13),ferulic acid(14),trans-p-hydroxycinnamic acid(15),cinnamic acid(16),vanillic acid(17),vanillin(18),4-hydroxyacetophenone(19),4-hydroxybenzaldehyde(20),apigenin(21),(-)-isolariciresinol(22),(-)-secoisolariciresinol(23)and meso-2,3-di(3′,4′-methylenedioxybenzyl)butane-1,4-diol(24).The IC50 values of compounds 3,5,7,8,19,and 20 ranged from(0.246 5±0.028 3)to(1.278 2±0.021 3)mmol/L.CONCLUSION Compounds 1-9、11、15、17-21、24 are isolated from this plant for the first time,and 1,6,9,17-19,24 are first isolated from genus Balanophora.Compounds 3、5、7、8、19 and 20 have tyrosinase inhibitory activity.

Aim To investigate the effects of Ixerin Z,a sesquiterpene lactone from Ixeris sonchifolia,on bone-lipid metabolic imbalance in ApoE-/-mice and to elu-cidate its molecular mechanisms.Methods A mouse model of ApoE-/-was induced using a high-fat diet,followed by eight weeks of Ixerin Z administration at doses of 1 and 10 mg·kg-1.Serum markers related to bone-lipid metabolism and inflammatory cytokines were quantified.Bone mineral density,biomechanical prop-erties,bone tissue morphology,and bone microstructure changes were analyzed.Computational molecular doc-king was performed to identify potential target proteins of Ixerin Z,and its regulatory effects on bone-lipid me-tabolism were investigated.Results Treatment with Ixerin Z markedly decreased the serum levels of total cholesterol,triglycerides,TNF-α,and IL-1β in ApoE-/-mice.It significantly improved bone mineral density,enhanced biomechanical strength,restored tra-becular structure,and reduced fat accumulation in bone tissue.Investigations revealed that Ixerin Z activated PPARα,thereby promoting fatty acid β-oxidation in bone tissue,and stimulating the Wnt/β-Catenin signa-ling pathway to facilitate bone formation.Furthermore,Ixerin Z suppressed the OPG/RANKL/NF-κB signaling pathway,leading to reduced bone resorption,independ-ent of PPARα activation.Conclusions Ixerin Z dem-onstrates potent therapeutic effects on bone-lipid meta-bolic imbalance in ApoE-/-mice.The mechanism in-volves activating PPARα to promote fatty acid β-oxida-tion in bone tissue,activating PPARα/Wnt/β-Catenin signaling pathway to promote bone formation,and in-hibiting OPG/RANKL/NF-κB signaling pathway to re-duce bone resorption.

AIM To study the chemical constituents from ethyl acetate fraction of Balanophora harlandii Hook.f.and their tyrosinase inhibitory activity.METHODS Separation and purification were performed using silica gel,MCI,ODS,Sephadex LH-20 and semi-preparative HPLC,then the structures of obtained compounds were identified by physicochemical properties and spectral data.The monophenolase inhibitory activity was determined by the tyrosinase-catalyzed oxidation of L-tyrosine.RESULTS Twenty-four compounds were isolated and identified as sesamin(1),methyl caffeate(2),quercetin(3),5,7-dihydroxychromanone(4),methyl 3,4-dihydroxybenzoate(5),esculetin(6),kaempferol(7),naringenin(8),pyrogallic acid(9),pinosylvin(10),methyl propionate(11),caffeic acid(12),saccharinol(13),ferulic acid(14),trans-p-hydroxycinnamic acid(15),cinnamic acid(16),vanillic acid(17),vanillin(18),4-hydroxyacetophenone(19),4-hydroxybenzaldehyde(20),apigenin(21),(-)-isolariciresinol(22),(-)-secoisolariciresinol(23)and meso-2,3-di(3′,4′-methylenedioxybenzyl)butane-1,4-diol(24).The IC50 values of compounds 3,5,7,8,19,and 20 ranged from(0.246 5±0.028 3)to(1.278 2±0.021 3)mmol/L.CONCLUSION Compounds 1-9、11、15、17-21、24 are isolated from this plant for the first time,and 1,6,9,17-19,24 are first isolated from genus Balanophora.Compounds 3、5、7、8、19 and 20 have tyrosinase inhibitory activity.

Objective:To evaluate the feasibility of transjugular transcatheter tricuspid valve replacement (TTVR) using the LuX-Valve Plus system (Ningbo Jenscare Scientific, China) for the treatment of severe tricuspid regurgitation in real-world clinical settings.Methods:This prospective study enrolled 81 patients with severe ricuspid regurgitation (≥3+) who underwent TTVR with the LuX-Valve Plus system at the Department of Cardiology, West China Hospital of Sichuan University between May 2022 and March 2024. Among them, 44 patients were from a compassionate-use study, and 37 were from two premarket clinical trials. Baseline clinical data, preprocedural imaging, procedural outcomes, and postprocedural follow-up data were collected. The primary endpoint events included device success, procedural success, and 30 d composite adverse events.Results:The age of the cohort was (74.5±7.8) years, with 54 females (67%). Device success and procedural success rates were both 90% (73/81). Post-procedural tricuspid regurgitation improved, with a 6% (5/81) incidence of moderate-to-severe paravalvular leakage. The rate of permanent pacemaker implantation was 12% (10/81), of which 5% (4/81) had pre-existing indications for pacemaker implantation. Major bleeding events occurred in 10% (8/81) of patients, and the 30 d composite endpoint rate was 25% (20/81).Conclusion:TTVR using the LuX-Valve Plus system demonstrates promising feasibility for high-risk surgical patients with severe tricuspid regurgitation, effectively reducing or eliminating regurgitation with acceptable safety. However, challenges remain in reducing risks of major adverse events, including permanent pacemaker implantation and severe bleeding.

Objective:To investigate the clinical efficacy and safety of ixazomib-containing regimens in the treatment of patients with multiple myeloma(MM).Methods:A retrospective analysis was performed on the clinical efficacy and adverse reactions of 32 MM patients treated with a combined regimen containing ixazomib in the Hematology Department of the First People's Hospital of Lianyungang from January 2020 to February 2022.Among the 32 patients,15 patients were relapsed and refractory multiple myeloma(R/RMM)(R/RMM group),17 patients who responded to bortezomib induction therapy but converted to ixazomib-containing regimen due to adverse events(AE)or other reasons(conversion treatment group).The treatment included IPD regimen(ixazomib+pomalidomide+dexamethasone),IRD regimen(ixazomib+lenalidomide+dexamethasone),ICD regimen(ixazomib+cyclophosphamide+dexamethasone),ID regimen(ixazomib+dexamethasone).Results:Of 15 R/RMM patients,overall response rate(ORR)was 53.3％(8/15),among them,1 achieved complete response(CR),2 achieved very good partial response(VGPR)and 5 achieved partial response(PR).The ORR of the IPD,IRD,ICD and ID regimen group were 100％(3/3),42.9％(3/7),33.3％(1/3),50％(1/2),respectively,there was no statistically significant difference in ORR between four groups(x2=3.375,P=0.452).The ORR of patients was 50％after first-line therapy,42.9％after second line therapy,60％after third line therapy or more,with no statistically significant difference among them(x2=2.164,P=0.730).In conversion treatment group,ORR was 88.2％(15/17),among them,6 patients achieved CR,5 patients achieved VGPR and 4 patients achieved PR.There was no statistically significant difference in ORR between the IPD(100％,3/3),IRD(100％,6/6),ICD(100％,3/3)and ID(60％,3/5)regimen groups(x2=3.737,P=0.184).The median progression-free survival(PFS)time of R/RMM patients was 9 months(95％CI:6.6-11.4 months),the median overall survival(OS)time was 18 months(95％CI:11.8-24.4 months).The median PFS time of conversion treatment group was 15 months(95％CI:7.3-22.7 months),the median OS time not reached.A total of 10 patients suffered grade 3-4 adverse event(AE).The common hematological toxicities were leukocytopenia,anemia,thrombocytopenia.The common non-hematological toxicities were gastrointestinal symptoms(diarrhea,nausea and vomit),peripheral neuropathy,fatigue and infections.Grade 1-2 peripheral neurotoxicity occurred in 7 patients.Conclusion:The ixazomib-based chemotherapy regimens are safe and effective in R/RMM therapy,particularly for conversion patients who are effective for bortezomib therapy.The AE was manageable and safe.

Objective To observe the efficacy and safety of Morinda officinalis oligosaccharides in the continuation treatment of mild and moderate depression.Methods An open,single-arm,multi-center design was adopted in our study.Adult patients with mild and moderate depression who had received acute treatment of Morinda officinalis oligosaccharides were enrolled and continue to receive Morinda officinalis oligosaccharides capsules for 24 weeks,the dose remained unchanged during continuation treatment.The remission rate,recurrence rate,recurrence time,and the change from baseline to endpoint of Hamilton Depression Scale(HAMD),Hamilton Anxiety Scale(HAMA),Clinical Global Impression-Severity(CGI-S)and Arizona Sexual Experience Scale(ASEX)were evaluated.The incidence of treatment-related adverse events was reported.Results The scores of HAMD-17 at baseline and after treatment were 6.60±1.87 and 5.85±4.18,scores of HAMA were 6.36±3.02 and 4.93±3.09,scores of CGI-S were 1.49±0.56 and 1.29±0.81,scores of ASEX were 15.92±4.72 and 15.57±5.26,with significant difference(P＜0.05).After continuation treatment,the remission rate was 54.59％(202 cases/370 cases),and the recurrence rate was 6.49％(24 cases/370 cases),the recurrence time was(64.67±42.47)days.The incidence of treatment-related adverse events was 15.35％(64 cases/417 cases).Conclusion Morinda officinalis oligosaccharides capsules can be effectively used for the continuation treatment of mild and moderate depression,and are well tolerated and safe.